FIELD OF THE INVENTION
The present invention provides certain enantiomerically pure aminoalcohol esters of arylcycloalkylhydroxycarboxylic acids, and processes for their preparation and medicinal use.
Esters of arylcycloalkylhydroxy acids with cyclic alcohols containing a quaternary nitrogen represented by formula I ##STR1##
comprising a hydroxycarboxylic acid component in which AR is an aromatic ring and in which R.sub.1 is a cycloaliphatic ring, and comprising an alcohol component in which the hydroxyl group is located on a dimethylpyrrolidinium ring (n=1) or dimethylpiperidinium ring (n=2) in which R.sub.2 =R.sub.3 is a lower alkyl and in which A is a halide, have in some instances been described as spasmolytics. If the two radicals R.sub.2 and R.sub.3 are identical, compounds of formula I have two chiral centers. One of the centers can be assigned to the acid moiety and relates to the position labeled 2', the second chiral center is located in the cyclic ring system at the position labeled 3. Since compounds of this structure accordingly have two chiral centers, four stereoisomers (3R,2'R; 3S,2'R; 3R,2'S and 3S,2'S) are possible in principle. To date, pure stereoisomers of the formula I compound have been neither isolated nor synthesized, nor have they been investigated pharmacologically--which is essential for the subject matter of the present patent application. The most important representative of the formula 1, which is also used in therapy, is glycopyrronium bromide (AR=phenyl, R.sub.1 =cyclopentyl, R.sub.2 =R.sub.3 =methyl, n=1, A=Br). The international non-proprietary name glycopyrronium bromide refers to the racemic mixture of diastereomers, which, accordingly, contains all four stereoisomers.
The publications and patents that have hitherto been published deal either with the drug glycopyrronium bromide in the form of a mixture of stereoisomers (CAS 596-51-0), with erythro-(RN 59677-73-5) or threo-(RN 59677-70-2) configured racemates of the tertiary amino ester (CRN 131118-11-1), which can be considered as only representing an intermediate in the synthesis of the compounds of the formula 1, or with the mixture of stereoisomers of the analogous cyclohexyl derivative (R.sub.1 =cyclohexyl) of the formula I (where n=1) (RN 101564-29-8). The publications quoted in Chemical Abstracts 80:53209h and 80:53214f describe the results of the analyses of the crystal structures of the compounds glycopyrronium bromide and hexapyrronium bromide which are in the form of mixtures of stereoisomers. The publications quoted in Chemical Abstracts 80:66587e, 80:66588f and 89.191258 describe the results of pharmacological investigations with the mixture of stereoisomers of the compound glycopyrronium bromide, or of combination products of this substance with neostigmine and pyridostigmine. The publications quoted in Abstracts 84:43164h and 85:32832u describe the partial separation of the mixture of stereoisomers by means of a crystallization with 5-nitroisophthalic acid and the study of the threo- or erythro-configured racemates already mentioned above by NMR. Here, the authors succeeded, starting from the mixture of stereoisomers (CRN 131118-11-1), only in separating the diastereomers into the two racemates, but they did not succeed in preparing the enantiomerically pure compounds. The publications quoted in Chemical Abstracts 96:219498m, 105:48928x, 113:158782t, 89:191258k and the European Patent EP 128886 A2 describe the results of studies on the chromatographic analysis of the mixture of stereoisomers of the compound glycopyrronium bromide and the preparation of the stationary phases used. A separation of the enantiomers or an isolation of the individual stereoisomers of the formula I is not reported in any of the above-mentioned publications. In all cases mentioned, HPL-chromatographic separation succeeded only at the stage of the diastereomers. Thus, the preparation of the enantiomerically pure compounds of the formula according to the present invention is not known from the prior art.
The pharmacological action of medicinal substances of formula I is based on their interaction with muscarinic acetylcholine receptors (muscarine receptors). They are therefore referred to as m-cholinoceptor antagonists or parasympatholytics or--owing to their relaxing effect on smooth muscles--as neurotropic spasmolytics. The multifarious effects of the parasympatholytics include: acceleration of the heart rate, reduced secretion of tears, saliva, perspiration, and of the glands of the digestive tract, relaxation of the smooth muscles of the bronchi, the gastrointestinal tract, the bile ducts, the urethra and the urinary bladder, pupil dilation and impairment of accommodation. Quaternary spasmolytics, which include the compounds of the formula I, do not cross the blood-brain barrier and therefore have no central activity. Depending on the mode of administration, the desired and undesired effects of parasympatholytics vary. If these substances are used as spasmolytics, the reduced secretion of saliva or pupil dilation, for example, will be referred to as side effect.
Based on recent research, it is known that the structure of muscarine receptors is not uniform, but that the pharmacological effects can be attributed to interactions with at least four different muscarine receptor subtypes. On the one hand, their distribution in different organs varies and, on the other hand, different muscarine receptor subtypes having different functions are involved in some neuronal signal transduction cascades. Various effects or side effects can be attributed to interactions with the different receptor subtypes, so that high subtype specificity is one of the aims in the development of modern spasmolytics.
Glycopyrronium bromide is an active compound which has been established for a long time but which does not meet the requirements of a "modern" therapeutic of this type. However, glycopyrronium bromide is not only a racemate but additionally a mixture of diastereomers in which, depending on the preparation process, the ratios of the individual isomers in the product can in fact vary. Such isomeric active compound mixtures may therefore show random subtype profiles, making targeted use difficult and provoking the occurrence of undesirable side effects.